Antipsychotics with Antidepressant Properties
Quetiapine, aripiprazole, and the olanzapine-fluoxetine combination are FDA-approved antipsychotics with proven antidepressant properties, while lurasidone is approved specifically for bipolar depression. 1, 2
FDA-Approved Agents for Depression
The following second-generation antipsychotics have received FDA approval for treating depressive disorders:
- Quetiapine (extended-release): Approved as adjunctive treatment to antidepressants in major depressive disorder and as monotherapy for bipolar depression 1, 2, 3
- Aripiprazole: Approved as adjunctive treatment to antidepressants in major depressive disorder 2, 3
- Olanzapine-fluoxetine combination: Approved for treatment-resistant depression and depressive episodes associated with bipolar I disorder 1, 3
- Lurasidone: Approved for bipolar depression 2
- Brexpiprazole and cariprazine: Also FDA-approved for adjunctive treatment of major depressive disorder 3
Critical Dosing Principle
These agents are effective for depression only at subantipsychotic doses. 2 Full antipsychotic doses are dysphorogenic (produce depression-like symptoms), so lower doses must be used when targeting depressive symptoms. 2
Comparative Efficacy in Treatment-Resistant Depression
Based on the most recent high-quality meta-analysis (2021), the relative effectiveness measured by number-needed-to-treat (NNT) shows: 4
- Lithium: NNT = 5 (most effective)
- Esketamine: NNT = 7
- Aripiprazole, olanzapine+fluoxetine, risperidone, ziprasidone: All NNT < 10
- Quetiapine: NNT = 13
- Brexpiprazole: NNT = 16
- Cariprazine: NNT = 16
Risk-Benefit Profile
The risk-benefit ratio (NNH/NNT) favors lithium (1.80) over esketamine (0.71) or SGAs (0.45), indicating lithium is both more effective and better tolerated. 4 However, among antipsychotics specifically: 4
- Brexpiprazole has the lowest adverse effect risk (NNH = 19)
- Quetiapine has the highest adverse effect risk (NNH = 3)
- Overall SGA adverse effect risk: NNH = 5
Mechanism and Receptor Profile
All second-generation antipsychotics may have anxiolytic effects at subantipsychotic doses due to their receptor profiles. 2 However, the antidepressant effect is not universal across all SGAs—it appears unique to quetiapine, aripiprazole, and possibly lurasidone, with direct evidence showing ziprasidone lacks significant antidepressant action. 2
Clinical Applications Beyond FDA Approval
Quetiapine shows strong evidence for use in major depressive disorder and generalized anxiety disorder, with preliminary support for treatment-resistant and psychotic depression. 5 It also demonstrates reasonable efficacy as an augmenting agent in obsessive-compulsive disorder. 5
Special Populations: Pediatric Use
For adolescents with bipolar disorder, the increased potential for weight gain and dyslipidemia compared with adults may lead clinicians to consider prescribing other drugs first. 1 Medication therapy for pediatric patients should only be undertaken after thorough diagnostic evaluation and careful consideration of potential risks. 1
Clozapine augmentation with an antidepressant can be considered for ongoing negative symptoms in schizophrenia. 6 For persistent negative symptoms, antidepressant augmentation may have beneficial effects even in the absence of a formal depression diagnosis, though benefits may be modest. 6
Common Pitfalls
- Avoid using full antipsychotic doses when targeting depression, as this produces dysphorogenic effects 2
- Do not assume all antipsychotics have antidepressant properties—this effect is specific to certain agents 2
- Monitor for metabolic side effects, particularly weight gain, akathisia, and tardive dyskinesia with long-term use 3
- Consider that typical antipsychotics may worsen depressive symptoms in patients with schizophrenia 7